Levodopa‐Induced Dyskinesia Are Mediated by Cortical Gamma Oscillations in Experimental Parkinsonism

Abstract

Background Levodopa is the most efficacious drug in the symptomatic therapy of motor symptoms in Parkinson's disease (PD); however, long‐term treatment is often complicated by troublesome levodopa‐induced dyskinesia (LID). Recent evidence suggests that LID might be related to increased cortical gamma oscillations. Objective The objective of this study was to test the hypothesis that cortical high‐gamma network activity relates to LID in the 6‐hydroxydopamine model and to identify new biomarkers for adaptive deep brain stimulation (DBS) therapy in PD. Methods We recorded and analyzed primary motor cortex (M1) electrocorticogram data and motor behavior in freely moving 6‐OHDA lesioned rats before and during a daily treatment with levodopa for 3 weeks. The results were correlated with the abnormal involuntary movement score (AIMS) and used for generalized linear modeling (GLM). Results Levodopa reverted motor impairment, suppressed beta activity, and, with repeated administration, led to a progressive enhancement of LID. Concurrently, we observed a highly significant stepwise amplitude increase in finely tuned gamma (FTG) activity and gamma centroid frequency. Whereas AIMS and FTG reached their maximum after the 4th injection and remained on a stable plateau thereafter, the centroid frequency of the FTG power continued to increase thereafter. Among the analyzed gamma activity parameters, the fraction of longest gamma bursts showed the strongest correlation with AIMS. Using a GLM, it was possible to accurately predict AIMS from cortical recordings. Conclusions FTG activity is tightly linked to LID and should be studied as a biomarker for adaptive DBS. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

Subthalamic deep brain stimulation induces finely-tuned gamma oscillations in the absence of levodopa

“…Moreover, when excessively exaggerated, FTG in the basal ganglia thalamo-cortical loop may contribute to involuntary movements, such as levodopa-induced dyskinesias in PD ( Swann et al, 2016 ), or dystonic posturing in isolated dystonia ( Miocinovic et al, 2018 ). The link to levodopa-induced dyskinesias has also been noted in animal models of Parkinsonism ( Güttler et al, 2020 ).…”

Mechanisms of Network Interactions for Flexible Cortico-Basal Ganglia-Mediated Action Control

“…This link was recently also confirmed in a rodent model of Parkinson's disease (Güttler et al, 2020).…”

Experimental Dopamine Reuptake Inhibitors in Parkinson’s Disease: A Review of the Evidence

“…It may also suitable for a better future understanding of l-dopa-induced motor complications, such as dyskinesia. [44][45][46] MPTP-, α-synuclein-and Parkin animal models recapitulate the progressive loss of dopamine neurons, the involvement of cortical and subcortical regions and other aspects of disease progression, even those involving the mesocorticolimbic system. [47][48][49] These employed in vitro and in vivo PD models may mirror the slow progression of neuronal dying, which asks for continuous adaptation of dopamine substitution in the clinical practice of the maintenance of PD patients.…”